rs17228641

Positions:

• chr15-32732607-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013372.7(GREM1):​c.*1362G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 245,032 control chromosomes in the GnomAD database, including 765 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.067 (428 hom., cov: 32)
  • Exomes 𝑓: 0.077 (337 hom.)
• Consequence: GREM1 NM_013372.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.553

Genes affected

GREM1 (HGNC:2001): (gremlin 1, DAN family BMP antagonist) This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. In mouse, this protein has been shown to relay the sonic hedgehog (SHH) signal from the polarizing region to the apical ectodermal ridge during limb bud outgrowth. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.*1362G>A		3_prime_UTR_variant	2/2	ENST00000651154.1
GREM1	NM_001191322.2	c.*1362G>A		3_prime_UTR_variant	3/3
GREM1	NM_001191323.2	c.*1362G>A		3_prime_UTR_variant	3/3
GREM1	NM_001368719.1	c.*1362G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.*1362G>A		3_prime_UTR_variant	2/2		NM_013372.7	P1
GREM1	ENST00000560830.1	c.*1362G>A		3_prime_UTR_variant	3/3	2
GREM1	ENST00000652365.1	c.*1362G>A		3_prime_UTR_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.0667 AC: 10142 AN: 152122 Hom.: 428 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0702

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0878

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.0837

GnomAD4 exome AF: 0.0765 AC: 7100 AN: 92792 Hom.: 337 Cov.: 0 AF XY: 0.0762 AC XY: 3274 AN XY: 42966

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.0600

Gnomad4 ASJ exome AF: 0.0722

Gnomad4 EAS exome AF: 0.000182

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0830

Gnomad4 NFE exome AF: 0.0980

Gnomad4 OTH exome AF: 0.0792

GnomAD4 genome AF: 0.0666 AC: 10144 AN: 152240 Hom.: 428 Cov.: 32 AF XY: 0.0645 AC XY: 4802 AN XY: 74432

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.0701

Gnomad4 ASJ AF: 0.0628

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0193

Gnomad4 FIN AF: 0.0878

Gnomad4 NFE AF: 0.0994

Gnomad4 OTH AF: 0.0829

Alfa AF: 0.0906 Hom.: 767

Bravo AF: 0.0643

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17228641; hg19: chr15-33024808;